Therapeutic Targeting of Telomerase in Lung Cancer Stem Cells

在之前的回顾期间，我们完成了针对非小细胞肺癌(NSCLC)端粒酶的I期和II期临床试验。这些试验的结果证实了调节端粒生物学是肺癌的一个重要靶点。与端粒较长的患者相比，端粒较短的非小细胞肺癌患者进展顺利，总体生存率较差。在我们完成的第二阶段试验中，我们确定端粒最短的患者对我们的端粒酶抑制剂有更好的总体反应。这些结果鼓励我们寻求其他新的机制来调节端粒生物学，这是这次更新项目的重点。我们还一直在进行非小细胞肺癌癌症干细胞生物标记物的临床前研究。我们已经确定ALDH1A1和ALDH1A3是肺癌干细胞的候选生物标记物，它们的表达与肺癌I期切除患者的不良预后相关。这些假定的癌症干细胞群体是端粒酶阳性的，具有激活的Wnt和HH激活途径，我们的实验支持了我们的端粒酶抑制剂不仅针对大部分肺癌细胞，而且还针对干细胞库的假设。我们也有针对ALDH的特异性抑制剂，并将在直接(细胞培养)异种移植瘤和ROCK抑制剂建立的原发肺癌中测试这些药物降低克隆性和致瘤性。 我们在能够将端粒酶抑制剂推向临床试验方面有着坚定的承诺和经过证明的记录。我们现在将推进我们的专利端粒酶抑制剂(端粒调节剂)和干细胞候选疗法。这将包括一种针对端粒相关蛋白tankyrase(PARP5A)的WNT抑制剂IWR-1。我们还将提出6-硫代-2‘脱氧鸟苷(6-硫代-DG)，这是一种基于核苷的端粒酶底物。与正常的端粒酶沉默细胞相比，6-硫代-DG和IWR-1处理都显示出对表达端粒酶的癌细胞的特异性增强。两者都会导致端粒缩短，并抑制体外和体内细胞的生长。我们的长期目标是最大化端粒缩短或去封顶，并确定在非小细胞肺癌患者临床上使用这些孢子开发的抑制剂的最有效方法。

In the previously review period we completed a Phase I and II clinical trial targeting telomerase in non-small cell lung cancer (NSCLC). The results of these trials validated modulating telomere biology as an important target in lung cancer. NSCLC patients with short telomeres have poorer progression free and overall survival compared to patients with longer telomeres. In our completed Phase II trial we determined that the patients with the shortest telomeres trended to having better overall responses to our telomerase inhibitor. These results have encouraged us to pursue other novel mechanisms to modulate telomere biology and this is the focus of this renewal project. We also have been conducting preclinical studies on cancer stem cell biomarkers in NSCLC. We have identified ALDH1A1 and ALDH1A3 as candidate lung cancer stem cell biomarkers whose expression correlates with a poor prognosis in lung cancer patients with resected Stage I disease. These putative cancer stem cell populations are telomerase positive with activated Wnt and Hh activated pathways and we have experimental support for the hypothesize that our telomerase inhibitors not only target the bulk of the lung cancer cells but also the stem cell pool. We also have specific inhibitors against ALDH and will test these for reducing clonogenicity and tumorigenicity in direct (never in cell culture) xenografts and in ROCK inhibitor established primary lung cancers. We have a strong commitment and proven track record of being able to advance telomerase inhibitors to clinical trials. We will now progress our patented telomerase inhibitors (telomere modulators) and stem cell candidate therapies. This will include a WNT inhibitor, IWR-1 that targets tankyrase (PARP5A), a telomere associated protein. We will also advance 6-thio-2'deoxyguanosine (6-thio-dG) that is a nucleoside-based telomerase substrate. Both 6-thio-dG and IWR-1 treatments show increased specificity to telomerase expressing cancer cells over normal telomerase silent cells. Both lead to telomere shortening and reduced in vitro and in vivo cell growth. Our long-term goal is to maximize telomere shortening or uncapping and to determine the most effective way to use these SPORE developed inhibitors clinically in patients with NSCLC.